Dependency of O-3 Induced Lung Mucus Hypersecretion on NQ01

O-3 诱导的肺粘液分泌过多对 NQ01 的依赖性

• 批准号: 7678999
• 负责人: W Michael Foster
• 金额: $ 34.04万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678999
• 关键词: Ablation; Acute; Air; Air Pollutants; Animal Model; Asthma; Biological Markers; Cell membrane; Cells; Chronic Obstructive Airway Disease; Cystic Fibrosis; Dependency; Disease; Enzymes; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelial Physiology; Epithelium; Etiology; Evaluation; Exposure to; Free Radicals; Generations; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Health; Human; Hydroquinones; Impairment; In Vitro; Inbred Mouse; Inflammatory; Injury; Integration Host Factors; Intervention; Investigation; Irritants; Laboratory Study; Leukocyte Elastase; Link; Lung; Lung Inflammation; MUC5AC gene; Mediator of activation protein; Membrane; Messenger RNA; Modeling; Morbidity - disease rate; Mucins; Mucociliary Clearance; Mucous body substance; Mus; NADP; NQO1 gene; Neutrophilia; Obstruction; Obstructive Lung Diseases; Oxidants; Oxidoreductase; Oxygen; Ozone; Pathway interactions; Patients; Phase; Phenotype; Physiology; Pneumonia; Production; Protein Biosynthesis; Proteins; Quinones; Reactive Oxygen Species; Research; Resistance; Respiratory physiology; Risk Factors; Secretory Cell; Single Nucleotide Polymorphism; Small Interfering RNA; Smog; Symptoms; Testing; Up-Regulation; Work; airway epithelium; airway obstruction; airway remodeling; cohort; human subject; hydroquinone; in vivo; lung injury; mRNA Expression; macrophage; mouse model; neutrophil; non-smoker; non-smoking; pulmonary function; respiratory; translational study

DESCRIPTION (provided by applicant): Recent epidemiologic studies have re-ignited an old controversy and opinions are forming as to whether mucus hypersecretion is crucial in the etiology of airway disease. For patients with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, mucus hypersecretion is now being considered as a risk factor for increased morbidity. The irritant and epithelial membrane effects of O3, a main component of urban smog, upon the airway, and in particular on mucin-type secretory cells and/or interaction with epithelial physiology, have not been investigated vigorously, and at best only superficially, in vivo. We have recently demonstrated in genetically diverse inbred mice that O3-induced pulmonary inflammation and up-regulation of lung mucin secretion and airway mucociliary clearance are host factor dependent. These results match translationally with our evaluations in humans where O3 exposure leads to alterations in mucociliary clearance, and release of a mediator(s) capable of increasing mucin protein synthesis and secretion in vitro. Importantly additional observations by us in a healthy cohort of non-smoking human subjects (n=135) demonstrates that a homozygotic genotype for a single nucleotide polymorphism of the quinone oxido-reductase enzyme, NQO1, protects from the acute irritant effects on air flow that occur with exposure to ambient levels of O3. We have also found that NQO1 can modulate synthesis of mucin proteins by airway epithelial cells in vitro; and in connection with host-factor dependency, that NQO1 is differentially expressed in mouse models susceptible and resistant to O3. As a working global hypothesis we propose that exposure to O3 by susceptible humans activates NQO1, generates reactive oxygen metabolites and leads to an increase in MUC5AC mRNA expression and production of mucins by airway epithelial cells. This cycle is re-initiated when O3-induced airway neutrophilia, leads to re-activation of NQO1 by neutrophil elastase, leading to expression and secretion of mucins, disordered mucociliary clearance, and reduced pulmonary function. Investigations are proposed for mouse models represented by an O3 susceptible strain, a lung mucin hypersecretion model, and a NQO1 deficient model and simultaneous with translational studies in humans that are segregated genetically between wild-type (NQO1 sufficient) and a single nucleotide polymorphism associated with NQO1 deficiency. The research plan is the initial step towards a definitive link between an ubiquitous urban air pollutant, and genetic factors that regulate oxidant-induced airway hypersecretion of mucus. PROJECT NARRATIVE: The research plan proposes translational studies in relevant animal models and human subjects in order to identify host (genetic) susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon, and aid in, understanding mechanisms regulating pro-oxidant lung injury, production and secretion of airway mucins, and clearance of respiratory mucus, and adverse health effects, that occur during and following exposure to airborne respiratory irritants.

描述（由申请人提供）：最近的流行病学研究重新引起了旧的争议，并且关于粘液分泌是否在气道疾病病因学至关重要的意见。对于哮喘，慢性阻塞性肺疾病（COPD）和囊性纤维化患者，现在被认为是粘液过度分泌是增加发病率的危险因素。 O3的刺激性和上皮膜作用（城市烟雾的主要组成部分）对气道，尤其是粘蛋白型分泌细胞和/或与上皮生理学的相互作用，并没有进行大力研究，并且最多只能从表面上进行vivo。最近，我们在遗传多种的近交小鼠中证明了O3诱导的肺部炎症和肺粘蛋白分泌的上调和气道粘膜纤毛间隙是宿主因子的依赖性。这些结果与我们在人类的评估上翻译匹配，在该人类中，O3暴露会导致粘膜钙清除的改变，并释放能够在体外增加粘蛋白蛋白质合成和分泌的介质（S）。重要的是，我们在不吸烟的人类受试者的健康队列中进行了其他观察（n = 135）表明，喹酮氧化氧化酶 - 还原酶酶NQO1的单核苷酸多态性的纯合性基因型可保护对空气流动的急性影响，从而免受对空气流动的影响，从而在曝光中会造成曝光范围的曝光水平。我们还发现，NQO1可以在体外通过气道上皮细胞调节粘蛋白蛋白的合成。并且与宿主因子依赖关系有关，NQO1在小鼠模型中差异表达，对O3具有抵抗力。作为一个有效的全球假设，我们提出，易感人类对O3的暴露会激活NQO1，产生活性氧代谢物，并导致MUC5AC mRNA表达和通过气道上皮细胞产生粘蛋白。当O3诱导的气道嗜中性粒细胞导致中性粒细胞弹性酶对NQO1重新激活时，该周期会重新生效，从而导致粘蛋白的表达和分泌，无序的粘膜钙清除率和降低的肺功能。提出了针对由O3易感性菌株，肺粘蛋白过度分泌模型以及NQO1缺陷模型表示的小鼠模型的研究，并同时与人类的转化研究同时进行了遗传型（NQO1足够）和单核苷酸多轴形在NQO1的遗传学之间的隔离。研究计划是朝着无处不在的城市空气污染物与调节氧化剂诱导的粘液过度分泌的遗传因素之间的确定性联系的第一步。项目叙述：研究计划提出了相关动物模型和人类受试者的翻译研究，以识别宿主（遗传）易感因素，这些因素赋予了原型空气污染物Ozone的脆弱性。结果将对调节促氧化肺损伤的机制有重大影响并有助于了解气道粘蛋白的产生和分泌以及呼吸道粘液的清除以及在暴露于空中呼吸道刺激物期间发生的情况下发生的不良健康作用。